RESUMO
Myelodysplastic syndromes (MDS) are acquired bone marrow malignant disorders characterized by ineffective hematopoiesis, resulting from a complex interaction between genetic and epigenetic mutations, alterations of the marrow microenvironment, and the immune system. In 2001, the World Health Organization (WHO) proposed a classification that integrates morphologic and genetic information, considering the MDS with ring sideroblasts (MDS-RS) as a distinct entity. Considering the strong association between MDS-RS and SF3B1 mutation and its importance in the development of MDS, the last WHO classification replaced the prior entity of MDS-RS with MDS with SF3B1 mutation. Several studies were performed to explore this genotype-phenotype correlation. Mutant SF3B1 protein deregulates the expression of genes implicated in developing hematopoietic stem and progenitor cells. Of paramount importance are PPOX and ABCB7 involved in iron metabolism. Another essential role in hemopoiesis is played by the transforming growth factor-beta (TGF-ß) receptor. This gene exerts its effects on SMAD pathways, regulating hematopoiesis through effects on balancing proliferation and apoptosis cell inactivity, differentiation, and migration. Luspatercept (ACE-536) is a soluble fusion protein that inhibits molecules in the TGF-ß superfamily. Since its structure resembles the TGF-ß family receptor, it catches TGF-ß superfamily ligands before binding to the receptor, resulting in reduced activation of SMAD signaling, thus enabling erythroid maturation. Luspatercept was investigated in the phase III trial MEDALIST, showing promising efficacy in treating anemia compared to placebo. Nowadays, further studies are needed to explore the real potential of luspatercept, investigating the biological features likely associated with treatment response, the potential use in combination treatments, and its role in the treatment of naïve MDS.
Assuntos
Anemia , Síndromes Mielodisplásicas , Humanos , Fatores de Processamento de RNA/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Medula Óssea/patologia , Mutação , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/uso terapêutico , Fosfoproteínas/genética , Fosfoproteínas/uso terapêutico , Flavoproteínas/genética , Flavoproteínas/uso terapêutico , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/uso terapêutico , Protoporfirinogênio Oxidase/genéticaRESUMO
NQO1 (DT-diaphorase) and its truncated isoenzyme, the metalloenzyme NQO2, can reduce quinone substrates by two-electron transfer. While NQO1 is a known detoxification enzyme, the function of NQO2 is less well understood. Both rat NQO1 and human NQO2 reductively bioactivate the dinitroarene CB 1954 to a cytotoxic product that behaves as a difunctional DNA-crosslinking species with potent anti-tumour activity, although human NQO1 is much less effective. A FMN-dependent nitroreductase from E. coli B also reduces quinones and reductively bioactivates CB 1954. However, this enzyme reduces CB 1954 to the 2- and 4-hydroxylamines in equivalent yield, whereas NQO1 and NQO2 generate only the 4-isomer. The reduction profile is a key factor in the development of anti-tumour prodrugs, where distinct delivery strategies are being evaluated: prodrug therapy, antibody-, macromolecule and gene-directed enzyme prodrug therapy (ADEPT, MDEPT or GDEPT). The flavoprotein enzymes are explored in terms of structure and bioreduction mechanism, particularly for use in the design of novel prodrugs with potential application as chemotherapeutic agents.
Assuntos
Antineoplásicos/uso terapêutico , Flavoproteínas/uso terapêutico , Quinona Redutases/metabolismo , Aerobiose , Antineoplásicos/síntese química , Antineoplásicos/química , Desenho de Fármacos , Transporte de Elétrons , Flavoproteínas/síntese química , Flavoproteínas/química , Terapia Genética , Humanos , Neoplasias/tratamento farmacológico , Nitratos/metabolismo , Nitritos/metabolismo , Oxirredução , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Quinona Redutases/genética , Relação Estrutura-AtividadeRESUMO
The authors studied feasibility of using flavours, particularly, agent M-1 containing basic nutrients of antipromotor action in available form and fish oil containing fatty omega-3 acids as well as natural vitamin E for correction of homeostasis in patients with gastrointestinal precancer. 142 patients at risk to develop gastrointestinal cancer received diets for 6 months by 2-month cycles: M-1 daily in a dose 15-50 g, fish oil in a dose 10-30 ml. Control subjects did not receive the diets. 6 months after the treatment start the test subjects exhibited regression of the disease in 36.6% the cases versus 14.1% in the controls. It is concluded that the above dietetic scheme promotes correction of antioxidant insufficiency and stabilization of cellular membranes in patients with mucosal dysplasia.